ALBUMIN MICROSPHERES AS A DRUG-DELIVERY SYSTEM - RELATION AMONG TURBIDITY RATIO, DEGREE OF CROSS-LINKING, AND DRUG-RELEASE

The degree of cross-linking of albumin microspheres, with and without drug, was assessed using turbidity measurements carried out in the presence of water and the protein denaturant guanidine hydrochloride (GuHCl) at a concentration that disrupted noncovalent bonds while having no effect on covalent bonds. The measurements allowed calculation of a turbidity ratio (T(G)/T(W)), expressed as the ratio of the turbidity of albumin microspheres in 6 M GuHCl (T(G)) divided by that in water (T(W)). A linear relation existed between T(G)/T(W) and the (i) temperature at which the microspheres were prepared, (ii) concentration of the cross-linking agent glutaraldehyde, and (iii) time of exposure to a second cross-linking agent, formaldehyde vapor, three conditions that increase the degree of cross-linking. The turbidity ratio also increased as the concentration of the albumin solution used to prepare the microspheres increased from 25 to 50%. Drug release from the microspheres consisted of an initial, rapid, burst followed by a second, slower, phase. The rates in both release phases were inversely related to the turbidity ratio, suggesting that this parameter has utility as an indicator of the degree of cross-linking in albumin microspheres.